Candidate: Dr. Carlsson's long-term goal is to become an independent clinical investigator in Alzheimer's disease (AD) and its relationship to vascular risk factors and vascular biology. As part of this Beeson Career Development Award (BCDA), Dr. Carlsson will develop a career in patient-oriented aging research by obtaining advanced training in clinical research design, biostatistics, cognitive theory and testing, and measures of cerebral perfusion by MRI through courses in the University of Wisconsin (UW) Graduate School, the UW Capstone Certificate Program in Fundamentals of Clinical Research, and workshops offered by the International Society for Magnetic Resonance in Medicine (ISMRM). She will also obtain advanced training in ethical and regulatory issues that govern human subjects research. Environment: The University of Wisconsin Medical School is a premier research institution that has identified Geriatrics and Neurosciences as 2 of the top 5 priority areas for research. In addition to the Wisconsin Comprehensive Memory Program and Section of Geriatrics and Gerontology, Dr. Carlsson will have access to the following resources for the proposed BCDA award: the Wisconsin Alzheimer's Institute the Wisconsin Registry for Alzheimer's Prevention; the VA Geriatric Research, Education and Clinical Center (GRECC); the UW General Clinical Research Center (GCRC); and 3T MR scanners in the UW Hospital and Waisman Laboratory for Brain Imaging. Research: Given the evidence from epidemiological, animal, and clinical research suggesting that statins may have a preventive role in AD, Dr. Carlsson proposes to evaluate the effect of simvastatin on cerebrospinal fluid (CSF) and plasma markers of AD progression, including CSF B-amyloid (AB) levels, central nervous system (CNS) cholesterol metabolism, and CNS inflammation in a population of middle-aged adults at increased risk for developing AD. In addition, she will evaluate the effects of simvastatin on cerebral perfusion and its integral relationship with these biomarkers. 100 men and women without dementia from the Wisconsin Registry for Alzheimer's Prevention will be recruited for participation in a 9-month randomized, controlled trial evaluating the effects of simvastatin 80 mg nightly vs. placebo on 1) CSF Ap levels; 2) plasma markers of CNS cholesterol metabolism; and 3) CSF and plasma markers of inflammation. Additionally, 50 participants will have a MRI to measure cerebral perfusion at baseline and month 9. Participants will have fasting labs drawn, CSF collected, and cognitive testing done at baseline and 9-month follow-up. Additional visits at 1, 3, and 6 months will assess side effects. Cognitive testing will also be repeated at the 3-month follow-up. Outcome measures at 9 months will be compared to baseline. Results will be analyzed by apolipoprotein E4 status.